Expedient Synthesis of Core Disaccharide Building Blocks from Natural Polysaccharides for Heparan Sulfate Oligosaccharide Assembly.

The complex sulfation motifs of heparan sulfate glycosaminoglycans (HS GAGs) play critical roles in many important biological processes. However, an understanding of their specific functions has been hampered by an inability to synthesize large numbers of diverse, yet defined, HS structures. Herein, we describe a new approach to access the four core disaccharides required for HS/heparin oligosaccharide assembly from natural polysaccharides. The use of disaccharides rather than monosaccharides as minimal precursors greatly accelerates the synthesis of HS GAGs, providing key disaccharide and tetrasaccharide intermediates in about half the number of steps compared to traditional strategies. Rapid access to such versatile intermediates will enable the generation of comprehensive libraries of sulfated oligosaccharides for unlocking the "sulfation code" and understanding the roles of specific GAG structures in physiology and disease.

Correction: Multivalent presentation of carbohydrates by 3(14)-helical peptide templates: synthesis, conformational analysis using CD spectroscopy and saccharide recognition.

Correction for 'Multivalent presentation of carbohydrates by 314-helical peptide templates: synthesis, conformational analysis using CD spectroscopy and saccharide recognition' by Nitin J. Pawar et al., Org. Biomol. Chem., 2015, 13, 11278-11285.

Multivalent presentation of carbohydrates by 3(14)-helical peptide templates: synthesis, conformational analysis using CD spectroscopy and saccharide recognition.

A well defined 314-helical tetravalent ß-galactopeptide site-specific functionalised template (SSFT) 1 was prepared containing d-galactose units, with free anomeric carbons as the aldehyde tags, and was explored via ligation with different aminoxy sugars (α-/ß-d-glucose, α/ß-d-galactose, α-d-mannose and ß-d-lactose) to get 314-helical carbohydrate-functionalised multivalent glycoconjugates 2-7. Preliminary recognition studies of tetramannosyl glycoconjugate 4 with a specific lectin (concanavalin A) using fluorescence anisotropy showed an increase in binding affinity and the multivalency effect was found to be increased by 6.5 times per glycan.

Molecular architecture with carbohydrate functionalized ß-peptides adopting 314-helical conformation.

Carbohydrate recognition is essential in cellular interactions and biological processes. It is characterized by structural diversity, multivalency and cooperative effects. To evaluate carbohydrate interaction and recognition, the structurally defined attachment of sugar units to a rigid template is highly desired. ß-Peptide helices offer conformationally stable templates for the linear presentation of sugar units in defined distances. The synthesis and ß-peptide incorporation of sugar-ß-amino acids are described providing the saccharide units as amino acid side chain. The respective sugar-ß-amino acids are accessible by Michael addition of ammonia to sugar units derivatized as α,ß-unsaturated esters. Three sugar units were incorporated in ß-peptide oligomers varying the sugar (glucose, galactose, xylose) and sugar protecting groups. The influence of sugar units and the configuration of sugar-ß-amino acids on ß-peptide secondary structure were investigated by CD spectroscopy.

Oxygen Imaging of a Rabbit Tumor Using a Human-Sized Pulse Electron Paramagnetic Resonance Imager.

PURPOSE: Spatial heterogeneity in tumor hypoxia is one of the most important factors regulating tumor growth, development, aggressiveness, metastasis, and affecting treatment outcome. Most solid tumors are known to have hypoxia or low oxygen levels (pO2 ≤10 torr). Electron paramagnetic resonance oxygen imaging (EPROI) is an emerging oxygen mapping technology. EPROI utilizes the linear relationship between the relaxation rates of the injectable OX071 trityl spin probe and the partial oxygen pressure (pO2). However, most of the EPROI studies have been limited to mouse models of solid tumors because of the instrument-size limitations. The purpose of this work was to develop a human-sized 9-mT (250 MHz resonance frequency, 60 cm bore size) pulse EPROI instrument and evaluate its performance with rabbit VX-2 tumor oxygen imaging. METHODS: A New Zealand white rabbit with a 3.2-cm VX-2 tumor in the calf muscle was imaged using the human-sized EPROI instrument and a 2.25-in. ID volume coil. The animal received a ~8-min intravenous injection of OX071 (5.2 mL total volume at 72 mM concentration) and, after 75 min, an intratumoral injection (120 µL total at 5 mM OX071 concentration) and underwent EPROI. At the end of the experiments, MRI was performed using a preclinical 9.4-T MRI system to outline the tumor boundaries. RESULTS: For the first time, a human-sized pulse EPROI instrument with a 60-cm bore size/250-MHz frequency was built and evaluated using rabbit tumor oxygen imaging. For the first time, the systemic IV injection of the oxygen-sensitive trityl OX071 spin probe was used for an animal of this size. The resulting EPROI image from the IV injection showed complete tumor coverage. The image obtained after intratumoral injection showed localized coverage in the upper lobe of the tumor, demonstrating the need for improved intratumoral injection protocol. CONCLUSIONS: This study demonstrates the performance of the world's first human-sized pulse EPROI instrument. It also demonstrates that the EPROI of larger animals can be performed using the systemic injection of a manageable amount of the spin probe. This brings EPROI one step closer to clinical applications in cancer therapies. Oxygen imaging is a platform technology, and the instrument and techniques developed here will also be useful for other clinical applications.

Inhibition of mitochondrial metabolism by (-)-jerantinine A: synthesis and biological studies in triple-negative breast cancer cells.

A concise semi-synthesis of the Aspidosperma alkaloids, (-)-jerantinine A and (-)-melodinine P, and derivatives thereof, is reported. The novel compounds were shown to have potent activity against MDA-MB-231 triple-negative breast cancer cells. Furthermore, unbiased metabolomics and live cell reporter assays reveal (-)-jerantinine A alters cellular redox metabolism and induces oxidative stress that coincides with cell cycle arrest.

α-Geminal dihydroxymethyl piperidine and pyrrolidine iminosugars: synthesis, conformational analysis, glycosidase inhibitory activity, and molecular docking studies.

The Jocic-Reeve and Corey-Link type reaction of dichloromethyllithium with suitably protected 5-keto-hexofuranoses followed by treatment with sodium azide and sodium borohydride reduction gave 5-azido-5-hydroxylmethyl substituted hexofuranoses 7a-c with required geminal dihydroxymethyl group. Removal of protecting groups and converting the C-1 anomeric carbon into free hemiacetal followed by intramolecular reductive aminocyclization with in situ generated C5-amino functionality afforded corresponding 5C-dihydroxymethyl piperidine iminosugars 2a-c. Alternatively, removal of protecting groups in 7b and 7c and chopping of C1-anomeric carbon gave C2-aldehyde that on intramolecular reductive aminocyclization with C5-amino gave 4C-dihydroxymethyl pyrrolidine iminosugars 1b and 1c, respectively. On the basis of the (1)H NMR studies, the conformations of 2a/2b were assigned as (4)C(1) and that of 2c as (1)C(4). The glycosidase inhibitory activities of all five iminosugars were studied with various glycosidase enzymes and compared with natural d-gluco-1-deoxynojirimycin (DNJ). All the five compounds were found to be potent inhibitors of rice α-glucosidase with K(i) and IC(50) values in the nanomolar concentration range. Iminosugars 2b and 1b were found to be more potent inhibitors than their parent iminosugar. These results were substantiated by in silico molecular docking studies.

Quaternary Indolizidine and Indolizidone Iminosugars as Potential Immunostimulating and Glycosidase Inhibitory Agents: Synthesis, Conformational Analysis, Biological Activity, and Molecular Docking Study.

New quaternary indolizidine iminosugars, with hydroxymethyl group at the ring junction, namely, C-8a-hydroxymethyl-1-deoxycastanospermine congeners 1a, 2a, 3a and their 3-oxo analogs 1b, 2b, and 3b were synthesized by using intramolecular reductive aminocyclization/lactamization of d-mannose/D-glucose derived C5-γ-azido esters as a key step wherein both the rings of the indolizidine skeleton were built up in one pot following the cascade reaction pathway. The conformations ((5)C8 or (8)C5) of 1-3 were assigned on the basis of the (1)H NMR studies. All compounds were found to be potent inhibitors of various glycosidase enzymes with Ki and IC50 values in the micromolar/nanomolar concentration range and further substantiated by molecular docking studies. The effect of synthesized iminosugars 1-3 on the cytokine secretion of IL-4, IL-6, and IFN-γ was evaluated. All compounds were found to be TH1 bias increasing the TH1/TH2 cytokines ratio (IL-6 and IL-4) indicating their potency as immunostimulating agents. Our study suggests that immunomodulatory activity of indolizidine iminosugars can be tuned by minor structural/stereochemical alterations.